一组广泛的微管相关蛋白质和激酶参与微管细胞骨架的协调调节,因此可能代表有价值的分子标记,有助于癌症中主要的细胞途径失调。我们先前鉴定了一组17个微管相关(MT-Rel)基因,这些基因在乳腺肿瘤中差异表达,显示出对基于紫杉烷的化疗的抗性。在本研究中,我们评估了表达式,这些基因在乳腺癌中的预后价值和功能影响。我们显示14个MT-Rel基因(KIF4A,ASPM,KIF20A,KIF14,TPX2,KIF18B,KIFC1,AURKB,KIF2C,与邻近正常组织相比,GTSE1,KIF15,KIF11,RACGAP1,STMN1)在乳腺肿瘤中上调。其中六个(KIF4A,ASPM,KIF20A,KIF14,TPX2,KIF18B)在肿瘤样品中过度表达超过10倍,其中四个(KIF11,AURKB,TPX2和KIFC1)对细胞存活至关重要。所有14个基因的过表达,3种其他MT-Rel基因(MAST4,MAPT和MTUS1)的低表达与乳腺癌患者的低生存率相关。系统生物学方法强调了连接17个MT-Rel基因及其伴侣的三个主要功能网络,以主轴组件为中心,染色体分离和胞质分裂。我们的研究将有丝分裂Aurora激酶及其底物确定为乳腺癌治疗方法的主要靶标。
A wide panel of microtubule-associated proteins and kinases is involved in coordinated regulation of the microtubule cytoskeleton and may thus represent valuable molecular markers contributing to major cellular pathways deregulated in cancer. We previously identified a panel of 17 microtubule-related (MT-Rel) genes that are differentially expressed in breast tumors showing resistance to taxane-based chemotherapy. In the present study, we evaluated the expression, prognostic value and functional impact of these genes in breast cancer. We show that 14 MT-Rel genes (KIF4A, ASPM, KIF20A, KIF14, TPX2, KIF18B, KIFC1, AURKB, KIF2C, GTSE1, KIF15, KIF11, RACGAP1, STMN1) are up-regulated in breast tumors compared with adjacent normal tissue. Six of them (KIF4A, ASPM, KIF20A, KIF14, TPX2, KIF18B) are overexpressed by more than 10-fold in tumor samples and four of them (KIF11, AURKB, TPX2 and KIFC1) are essential for cell survival. Overexpression of all 14 genes, and underexpression of 3 other MT-Rel genes (MAST4, MAPT and MTUS1) are associated with poor breast cancer patient survival. A Systems Biology approach highlighted three major functional networks connecting the 17 MT-Rel genes and their partners, which are centered on spindle assembly, chromosome segregation and cytokinesis. Our studies identified mitotic Aurora kinases and their substrates as major targets for therapeutic approaches against breast cancer.